Preparation Of Nitric Oxide Prodrug Nanomaterials And Their Application In Tumor Therapy

The high morbidity and the death rate of tumours are a serious threat to human health.The current situation of multidrug resistance and hypoxia during tumour treatment has greatly reduced the effectiveness of tumour therapy.Nitric oxide(NO)plays a variety of roles in tumour treatments,including direct anti-tumour effects,chemotherapy sensitisation and enhancing tumour oxygen supply.In view of the important functions of NO in tumour therapy,however NO is a gaseous with a short half-life.It is crucial to deliver NO to tumours,improve the bioavailability of NO in tumours and minimize its toxic side effects on normal tissues,and the development of nano-drug carriers has pointed the way for the delivery and treatment of NO to tumours.Based on this,we propose to construct two drug carriers,peptide nanofiber hydrogels and polymeric nanomicelles,for the efficient co-delivery of NO and drugs to tumors,and to exploit the function of NO in overcoming tumor drug resistance and hypoxia,aiming to achieve efficient synergistic anti-tumor effects of NO and drugs.Details of the studies are as follows:(1)Co-delivery of NO prodrugs and the antitumour drug adriamycin(DOX)for chemotherapy of locally drug-resistant tumours by peptide nanofibre hydrogels as drug carriers.An injectable nanofibrous peptide hydrogel Nap FFGEE-JSK/DOX was synthesized for NO and DOX co-delivery by electrostatic adsorption co-loading of glutamate in the peptide with the chemotherapeutic drug DOX and self-assembly by intermolecular hydrophobic and hydrogen bonding interactions between the peptides.The hydrogel consists of nanopeptide fibres with a diameter of approximately 20-40 nm and an energy storage modulus of 400 Pa,which can be used for local injectable drug delivery to tumours.The results showed that the hydrogel nanofibres were readily taken up by the tumour cells and that the hydrogel stimulated the release of NO and DOX in response to high GSH/GST expression and acidic in the tumour cells for up to72 h and 60 h.The delivery of NO and DOX in peptide hydrogels as carriers increased the accumulation of both drugs in the tumour compared to small molecule drugs.The anti-tumour results showed that NO activated mitochondria-mediated apoptosis and exerted direct anti-tumour effects on the one hand;on the other hand,NO reduced Pgp-mediated DOX efflux and NO exerted both sensitizing DOX chemotherapy-resistant tumour effects.The peptide hydrogels effectively improved the bioavailability of NO and DOX and provided a new idea for tumour chemoresistant sensitisation.(2)Biodegradable polymeric micelles were employed as nanodrug carriers for the co-delivery of the NO prodrug JSK and the photosensitizer desmet chlorophyllate A(Pheo A)for enhancing photodynamic antitumor efficacy.Covalently modified poly(ethylene glycol)-SS-polycaprolactone amphiphilic polymer JSK-CSSE-Pheo A,which was covalently modified with the NO prodrug JSK and the photosensitizer Pheo A,was synthesized,and its self-assembled nanomicelles were prepared by hydrophobic interaction.The particle size of the micelles was approximately 168 nm,with the hydrophobic JSK distributed in the hydrophobic cavities of the micelles and Pheo A distributed on the hydrophilic surface in an aggregated and quenched state.The results of drug release showed that under the high concentration of GSH in the tumour,the-SS-bond in the polymer was broken,the micelles disintegrated and released Pheo A,which changed from the quenched state to the activated state and increased the ROS yield of Pheo A under near infrared light(NIR).Collagen degradation,alleviated tumor hypoxia and sensitized the photodynamic antitumor effect of Pheo A.The nanomedicine effectively enhanced the bioavailability of NO and photosensitizers and provided a theoretical basis for NO-enhanced photodynamic antitumour therapy.